This application is the National Phase of PCT/US97/05160 filed on Mar. 28, 1997.
The present invention relates to new compositions useful in treating parasitic and opportunistic infections. Additionally, the present invention relates to the use of enantiomers of 8-aminoquinoline compounds for the treatment of Pneumocystis carinii, pneumonia (PCP), toxoplasmosis, malaria, trypanosomaiasis, and leishmaniasis in mammals and the prevention of PCP and malaria in mammals.
Parasitic diseases are a major health problem in the world. Malaria, due to one of four Plasmodium species, is the most widespread parasitic disease, with a reported total of 100 million clinical cases that lead to more than 1 million deaths annually. Trypanosomiases are diseases caused by the protozoa of the genus Trypanosoma. Two major forms of this disease occur in man: African trypanosomiasis (sleeping sickness) and American trypanosomiasis (Chagas disease). Some 16-18 million people are infected with T. cruzi, the cause of American trypanosomiasis, and it is estimated that 50 million people in some 36 countries are at risk of contracting African sleeping sickness [Ann. Trop. Med. Parasitol. 85, 43 (1991) M. L. Ruiz et al.]. Leishmaniases are a group of human parasitic diseases caused by protozoa of the genus Leishmania and are manifested in three major forms: cutaneous, mucocutaneous, and visceral. Visceral leishmaniasis, due mainly to Leishmania donovani, is fatal if untreated. Current therapies for this and the other parasitic diseases suffer significant shortcomings.
In addition to the significant morbidity and mortality associated with the parasitic infections, with the advent of AIDS epidemic, opportunistic parasitic diseases such as Pneumocystis carinii pneumonia, toxoplasmosis and cryptosporidiosis have become the leading cause of death among AIDS patients throughout the world. The non-availability of safe and efficacious drugs and drug resistance have hampered the effective treatment of all of these diseases.
Primaquine is an 8-aminoquinoline and the drug of choice for the radical cure of relapsing malaria [Drugs, 39, 160(1990) D. M. Panisko et al. ibid 39, 337(1990) J. S Keystone] caused by Plasmodium vivax and P. ovale and is also being used as a prophylactic against all major forms of human malaria [Am. J. Trop. Med. Hyg. (supp), 49(3), Abrs. 417(1990) J. K. Baird et al.]. This drug was found to have significant sporontocidal and gametocytocidal [Military Med., 134, 802-819(1969) K. H. Rieckmann et al.] activity but very low activity against blood stage malaria parasites at therapeutic doses [Prog. Med. Chem., 28, 1(1991) E. A. Nodiff et al.]. Moreover, primaquine is reported to be active in animal models of other parasitic infections, including Trypanosomiasis [PQ Activity vs. Trypanosoma, J. Parasit., 74, 748 (1988) R. E. McCabe]. In addition to its activity against the parasitic infections, primaquine in combination with clindamycin has been successfully used for the treatment as well as prophylaxis of Pneumocystis carinii pneumonia in AIDS patients [South. Med. J., 83, 403(1990) R. Kay et al.; Lancet i, 1046(1989) E. Toma et al.; Clin. Infect. Dis., 14: 183(1992) G. S. Noskinm et al.]. This drug has also shown significant activity against other disease causing parasites such as Trypanosoma [J. Parasit., 74, 748(1988) R. E. McCabe] and Leishmanic [Am. J. Trop. Med. Hyg., 32, 753(1983) D. J. Berman et al.]. D. J. Berman et al.]. There are three reports on the use of primaquine for the treatment of Trypanosoma cruzi infection in humans [J. Parasit., 74, 748(1988) R. E. McCabe]. The major limitation of primaquine and other 8-aminoquinoline antimalarials is that they cause methemoglobinemia [N. Engl. J. Med., 279, 1127(1968) R. J. Cohen et al.] and hemolysis [Arch. Intern. Med. 109, 209(1962) A. R. Tarlov et al.] in individuals who suffer from glucose-6-phosphate dehydrogenase deficiency.
Over the years, several attempts have been made to improve the therapeutic index of primaquine against malaria and Leishmania through modification of its chemical structure. Introduction of 4-methyl and 5-phenoxy [J. Med. Chem. 25, 1094(1982) M. P. LaMontagne et al.; ibid, 25, 1097(1982) E. A. Nodiff et al.] or alkoxy groups [J. Med. Chem. 30, 1193(1987) E. H. Chen et al.] have produced analogs with much superior tissue and blood schizonticidal activity. However, toxicity studies have shown that these analogs also have a greater potential of producing methemoglobin [Fundam. Appl. Toxicol., 10, 270(1988) J. Anders et al.]. Recently, LaMontagne [J. Med. Chem., 32, 1728(1989) M. P. LaMontagne et al.] has reported that introduction of a methoxyl at position 2 of the quinoline ring reduces the toxicity of some of these compounds, especially induction of methemoglobin, without losing activity. Based on these results, the US Army selected an 8-aminoquinoline derivative, WR-238,605, as a potential replacement for primaquine for the treatment of relapsing malaria [Pharm. Res., 8, 1505(1991) R. P. Brueckner at el.].
Similarly, the US Army had selected WR-6026, a 4-methylprimaquine analog, as a potential drug for the treatment of leishmaniasis [Xenobiotica, 20, 31(1990) L. A. Shipley et al.]. Since the compound WR-6026 was selected as the potential candidate for the treatment of leishmaniasis in 1978 [Am. J. Trop. Med. Hyg., 27, 751(1978) K. E. Kinnamon et al.], a large number of 5-phenoxy or 5-alkoxy-4-methylprimaquine analogs have been synthesized. Some of these analogs have shown higher antileishmanial activity than WR-6026 in an in vitro assay [Am. J. Trop. Med. Hyg., 32, 753(1983) D. J. Berman et al.].
After the first report [Antimicrob. Ag. Chemotherap., 32, 807(1988) S. F. Queener et al.] of antipneumocystis activity of primaquine in combination with clindamycin, several other 8-aminoquinolines were evaluated for antipneumocystic activity [Antimicrob. Ag. Chemotherap., 34: 277(1991) M. S. Bartlett et al.; ibid., 37, 2166(1993) S. Queener] and some of them, even when used alone, were found to be superior to the primaquine/clindamycin combination.
The effect of isomerism on biological activity and toxicity is well documented. However, this phenomenon has received little attention in the case of the 8-aminoquinolines. Schmidt et al [Antimicrob. Ag. Chemotherap., 12, 51 (1977) L. H. Schmidt] examined the relative curative and toxic activities of primaquine and its d- and l-_isomers in mice and rhesus monkeys. They confirmed an earlier report that d-primaquine was approximately 4 times as toxic as the l-form in mice but that the opposite is true in the rhesus monkey in which the l-form was 3 to 5 times as toxic as the d-primaquine and at least twice as toxic as, in which racemic primaquine. More importantly, all three forms of primaquine, the d- and l- and dl-, showed essentially identical curative properties against sporozoite induced P. cynomolgi infections. In studies on the metabolism of d- and l-isomers it was shown that the metabolic rates for the d- and l- isomers were different [J. Pharm. Sci., 77, 380(1988) J. K. Baker et al.]. Several other studies also have shown different activities and toxicities for d- and l-isomers [Biochem. Pharmacol., 37: 4605(1988) S. Agarwal et al.; FEBS Letts., 214, 291(1987) A. Brossi et al.]
The present invention relates to new and more active and/or less toxic compositions for the treatment of parasitic and opportunistic infections and diseases. These compositions comprise enantiomerically pure stereoisomers or mixtures of stereoisomers of 8-aminoquinoline analogs with the best activity and toxicity profile for the treatment and prevention of Pneumocystis carinii pneumonia (PCP), toxoplasmosis, malaria, trypanosomaiasis, and leishmaniasis in mammals.
The present invention relates to improvements in the chemotherapy of parasitic diseases through the separation of racemic 8-aminoquinoline compounds with desirable activity and toxicity profiles into pure enantiomers and the selection of the pure enantiomer with improved therapeutic and/or toxicity profile for enhanced treatment.
A number of compounds of the 8-aminoquinoline class were synthesized and their anti-parasitic activities were evaluated by administration of the test compounds to mice orally, in multiple doses. Compounds with optimum therapeutic and toxicity profiles were chosen, separated into enantiomers and the activity profile of the each enantiomer was determined. Surprisingly it was observed that (xe2x88x92) enantiomer of DN3-27-1 possessed significantly greater activity than the (+) enantiomer in the mouse model of PCP. It is speculated that the active enantiomer is responsible for the observed activity of DN3-27-1 at minimum effective doses. Hence, the present invention comprises the use of enantiomerically pure 8-aminoquinolines other than primaquine for the enhanced treatment of parasitic infections and diseases including opportunistic parasitic infections and diseases. The invention also encompasses new aminoquinolines which have not previously been described.